Characterization of a Heparan Sulfate Octasaccharide That Binds to Herpes Simplex Virus Type 1 Glycoprotein D

Liu, Jian; Shriver, Zach; Pope, R. Marshall; Thorp, Suzanne C.; Duncan, Michael B.; Copeland, Ronald J.; Raska, Christina S.; Yoshida, Koichiro; Eisenberg, Roselyn J.; Cohen, Gary H.; Linhardt, Robert J.; Sasisekharan, Ram

doi:10.1074/jbc.m202034200

Cited by 153 publications

(126 citation statements)

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“…The K d for the 3-O-[ 35 S]sulfated octasaccharide to gD was determined to be 19 μM (Fig. 3B), which is very similar to the K d of a previously characterized gD binding 3-O-sulfated octasaccharide isolated from HS (18 μM) (25).…”

Section: Determination Of the Binding Affinity Of The 3-o-sulfated Ocsupporting

confidence: 53%

“…The structure of the 3-O-sulfated octasaccharide is ΔUA2S-GlcNS6S-IdoUA2S-GlcNS6S-IdoUA2S-GlcNS3S6S-IdoUA2S-GlcNS6S as determined by the mass spectrometry and sequencing analysis. This octassccharide is structurally distinct from a previous HSderived octasaccharide, ΔUA-GlcNS-IdoUA2S-GlcNAc-UA2S-GlcNS-IdoUA2S-GlcNH 2 3S6S (where Ac is acetyl and UA is either glucuronic or iduronic acid), which was synthesized through a completely different route (25). The previous structure was prepared in extremely small quantities from 3-OST-3 enzyme modified HS hexasaccharide library.…”

Section: Discussionmentioning

confidence: 99%

“…This receptor is unique as it is a polysaccharide and contains a specific saccharide structure. Further structural analysis of a gD-binding oligosaccharide revealed that the binding of HS to gD requires a 3-O-sulfated glucosamine unit (25).…”

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confidence: 99%

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Using a 3-O-Sulfated Heparin Octasaccharide To Inhibit the Entry of Herpes Simplex Virus Type 1

et al. 2008

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Heparan sulfate (HS) is a highly sulfated polysaccharide and is present in large quantities on the cell surface and in the extracellular matrix. Herpes simplex virus type 1(HSV-1) utilizes a specialized cell surface HS, known as 3-O-sulfated HS, as an entry receptor to establish infection. Here, we exploit an approach to inhibit HSV-1 infection by using a 3-O-sulfated octasaccharide, mimicking the active domain of the entry receptor. The 3-O-sulfated octasaccharide was synthesized by incubating a heparin octasaccharide (3-OH octasaccharide) with HS 3-O-sulfotransferase isoform 3. The resultant 3-O-sulfated octasaccharide has a structure of ΔUA2S-GlcNS6S-IdoUA2S-GlcNS6S-IdoUA2S-GlcNS3S6S-IdoUA2S-GlcNS6S (where ΔUA is 4-deoxy-α-L-threo-hex-4-enopyranosyluronic acid, GlcN is D-glucosamine and IdoUA is L-iduronic acid). Results from cell based assays revealed that the 3-O-sulfated octasaccharide has stronger activity in blocking HSV-1 infection than that of the 3-OH octasaccharide, suggesting that the inhibition of HSV-1 infection requires a unique sulfation moiety. Our results suggest the feasibility of inhibiting HSV-1 infection by blocking viral entry with a specific oligosaccharide. KeywordsHeparin; heparan sulfate; herpes simplex virus; glycoprotein D; sulfotransferase; oligosaccharides Heparan sulfate (HS) is a highly sulfated linear polysaccharide present ubiquitously on the cell surface and in the extracellular matrix. HS plays a role in regulating embryonic development, inflammatory response, blood coagulation and assisting viral/bacterial infections (1). Heparin, a commonly used anticoagulant drug, is a special form of HS containing glucuronic (GlcUA)/ iduronic acid (IdoUA) and glucosamine, each carrying sulfo groups (Fig. 1A). The uniquely distributed sulfation pattern of HS polysaccharide is believed to regulate its functional specificity (2-4). Thus, understanding the structure and function relationship of HS attracts considerable interest in improving the anticoagulant efficacy of heparin and exploiting heparin *Corresponding author: Rm 309, Beard Hall, University of North Carolina, Chapel Hill, NC 27599. Tel.: 919-843-6511; Fax: 919-843-5432; E-mail: jian_liu@unc.edu. NIH Public Access Author ManuscriptBiochemistry. Author manuscript; available in PMC 2009 May 27. Published in final edited form as:Biochemistry. 2008 May 27; 47(21): 5774-5783. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript or heparin-like molecules for the development of anticancer and antiviral drugs (5-7). The major difficulty in dissecting the structure and function relationship of HS is to obtain HS oligosaccharides or polysaccharides with defined structures. Chemical synthesis has been the major route to prepare structurally defined oligosaccharides to mimic the functions of HS. However, the synthesis of those molecules larger than hexasaccharides is extremely difficult. Using HS biosynthetic enzymes to prepare biologically active polysaccharides and oligosaccharides has recently gained momentum...

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Section: Determination Of the Binding Affinity Of The 3-o-sulfated Ocsupporting

confidence: 53%

Section: Discussionmentioning

confidence: 99%

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Using a 3-O-Sulfated Heparin Octasaccharide To Inhibit the Entry of Herpes Simplex Virus Type 1

et al. 2008

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“…Furthermore, the heparanase and NO cleavage sites in Gpc-1 HS chains are often located close together (27). Interestingly, a HS octasaccharide segment that binds to glycoprotein D of herpes simplex virus type 1 contains a GlcNH 3 ϩ residue that is both 3-and 6-O-sulfated, and at the nonreducing side of this residue, there is a 2-O-sulfated iduronic acid (40). The next uronic acid upstream should be a sulfated glucuronic acid.…”

Section: Discussionmentioning

confidence: 99%

Glypican-1 Is a Vehicle for Polyamine Uptake in Mammalian Cells

Belting

Mani

Jönsson

et al. 2003

Journal of Biological Chemistry

151

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Polyamines (putrescine, spermidine, and spermine) are essential for growth and survival of all cells. When polyamine biosynthesis is inhibited, there is up-regulation of import. The mammalian polyamine transport system is unknown. We have previously shown that the heparan sulfate (HS) side chains of recycling glypican-1 (Gpc-1) can sequester spermine, that intracellular polyamine depletion increases the number of NO-sensitive N-unsubstituted glucosamines in HS, and that NO-dependent cleavage of HS at these sites is required for spermine uptake. The NO is derived from S-nitroso groups in the Gpc-1 protein. Using RNA interference technology as well as biochemical and microscopic techniques applied to both normal and uptake-deficient cells, we demonstrate that inhibition of Gpc-1 expression abrogates spermine uptake and intracellular delivery. In unperturbed cells, spermine and recycling Gpc-1 carrying HS chains rich in Nunsubstituted glucosamines were co-localized. By exposing cells to ascorbate, we induced release of NO from the S-nitroso groups, resulting in HS degradation and unloading of the sequestered polyamines as well as nuclear targeting of the deglycanated Gpc-1 protein. Polyamine uptake-deficient cells appear to have a defect in the NO release mechanism. We have managed to restore spermine uptake partially in these cells by providing spermine NONOate and ascorbate. The former bound to the HS chains of recycling Gpc-1 and S-nitrosylated the core protein. Ascorbate released NO, which degraded HS and liberated the bound spermine. Recycling HS proteoglycans of the glypican-type may be plasma membrane carriers for cargo taken up by caveolar endocytosis.

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“…Other reports showed the broad spectrum of "in vitro" activity of heparin on a variety of RNA and DNA viruses [58,59]. As for other therapeutic applications, anticoagulant activity limited doses, poor pharmacokinetics and the poor oral absorption of heparin were the major drawbacks to further developments.…”

Section: Other Experimentally Investigated Activitiesmentioning

confidence: 99%